Stephen Joy

Stephen Joy

Post Graduate Research Assistant
University of MIchigan
Ann Arbor, MI


A Highly Potent and Selective Inhibitor of the Myb- KIX Interaction

Acute myeloid leukemia, AML, is dependent on the native interaction between the transcriptional activator Myb and the transcriptional coactivator CREB-binding protein, CBP. The CBP coactivator interacts with a variety of different transcription factors through its flexible KIX domain, allowing CBP to control transcription of many genes. Unfortunately, the conformational plasticity and the presence of multiple binding sites on KIX make it challenging to target using small molecule inhibitors. Notably, the transactivation domains of Myb and MLL bind to two different sites on KIX, and fusing these two domains via a flexible linker produces a peptide, MybLL-tide, that has picomolar affinity for KIX.

MybLL-tide has higher affinity for KIX than any previously reported compounds while also possessing 15,000-fold selectivity for the CBP KIX domain over other similar coactivator domains. Further modification of the MybLL-tide with a nuclear localization signal and a cell penetrating peptide moiety yield a modified MybLL-tide with cellular activity that potently modulates downstream gene expression and also inhibits AML cell viability. These promising results show that MybLL-tide can be an effective, modifiable tool to selectively target the KIX domain and assess transcriptional effects in both AML cells and potentially other cancers dependent on aberrant Myb or MLL behavior.

Lecture Images

Stephen Joy presenting at APS2019 Stephen Joy presenting at APS2019 Stephen Joy presenting at APS2019